Development of an international standard set of outcome measures for patients with atrial fibrillation: a report of the International Consortium for Health Outcomes Measurement (ICHOM) atrial fibrillation working group.

AIMS: As health systems around the world increasingly look to measure and improve the value of care that they provide to patients, being able to measure the outcomes that matter most to patients is vital. To support the shift towards value-based health care in atrial fibrillation (AF), the International Consortium for Health Outcomes Measurement (ICHOM) assembled an international Working Group (WG) of 30 volunteers, including health professionals and patient representatives to develop a standardized minimum set of outcomes for benchmarking care delivery in clinical settings. METHODS AND RESULTS: Using an online-modified Delphi process, outcomes important to patients and health professionals were selected and categorized into (i) long-term consequences of disease outcomes, (ii) complications of treatment outcomes, and (iii) patient-reported outcomes. The WG identified demographic and clinical variables for use as case-mix risk adjusters. These included baseline demographics, comorbidities, cognitive function, date of diagnosis, disease duration, medications prescribed and AF procedures, as well as smoking, body mass index (BMI), alcohol intake, and physical activity. Where appropriate, and for ease of implementation, standardization of outcomes and case-mix variables was achieved using ICD codes. The standard set underwent an open review process in which over 80% of patients surveyed agreed with the outcomes captured by the standard set. CONCLUSION: Implementation of these consensus recommendations could help institutions to monitor, compare and improve the quality and delivery of chronic AF care. Their consistent definition and collection, using ICD codes where applicable, could also broaden the implementation of more patient-centric clinical outcomes research in AF

On-treatment comparison between corrective His bundle pacing and biventricular pacing for cardiac resynchronization: A secondary analysis of His-SYNC

Background The His-SYNC pilot trial was the first randomized comparison between His bundle pacing in lieu of a left ventricular lead for cardiac resynchronization therapy (His-CRT) and biventricular pacing (BiV-CRT), but was limited by high rates of crossover. Objective To evaluate the results of the His-SYNC pilot trial utilizing treatment-received (TR) and per-protocol (PP) analyses. Methods The His-SYNC pilot was a multicenter, prospective, single-blinded, randomized, controlled trial comparing His-CRT vs BiV-CRT in patients meeting standard indications for CRT (eg, NYHA II–IV patients with QRS >120 ms). Crossovers were required based on prespecified criteria. The primary endpoints analyzed included improvement in QRS duration, left ventricular ejection fraction (LVEF), and freedom from cardiovascular (CV) hospitalization and mortality. Results Among 41 patients enrolled (aged 64 ± 13 years, 38% female, LVEF 28%, QRS 168 ± 18 ms), 21 were randomized to His-CRT and 20 to BiV-CRT. Crossover occurred in 48% of His-CRT and 26% of BiV-CRT. The most common reason for crossover from His-CRT was inability to correct QRS owing to nonspecific intraventricular conduction delay (n = 5). Patients treated with His-CRT demonstrated greater QRS narrowing compared to BiV (125 ± 22 ms vs 164 ± 25 ms [TR], P < .001;124 ± 19 ms vs 162 ± 24 ms [PP], P < .001). A trend toward higher echocardiographic response was also observed (80 vs 57% [TR], P = .14; 91% vs 54% [PP], P = .078). No significant differences in CV hospitalization or mortality were observed. Conclusions Patients receiving His-CRT on-treatment demonstrated superior electrical resynchronization and a trend toward higher echocardiographic response than BiV-CRT. Larger prospective studies may be justifiable with refinements in patient selection and implantation techniques to minimize crossovers

Circadian variability patterns predict and guide premature ventricular contraction ablation procedural inducibility and outcomes

Background Infrequent intraprocedural premature ventricular complexes (PVCs) may impede radiofrequency catheter ablation (RFA) outcome, and pharmacologic induction is unpredictable. Objective The purpose of this study was to determine whether PVC circadian variation could help predict drug response. Methods Consecutive patients referred for RFA with detailed Holter monitoring and frequent monomorphic PVCs were included. Patients were divided into 3 groups based on hourly PVC count relationship to corresponding mean heart rate (HR) during each of the 24 hours on Holter: fast-HR-dependent PVC (F-HR-PVC) type for a positive correlation (Pearson, P <.05), slow-HR-dependent PVC (S-HR-PVC) type for a negative correlation, and independent-HR-PVC (I-HR-PVC) when no correlation was found. Results Fifty-one of the 101 patients (50.5%) had F-HR-PVC, 39.6% I-HR-PVC, and 9.9% S-HR-PVC; 30.7% had infrequent intraprocedural PVC requiring drug infusion. The best predictor of infrequent PVC was number of hours with PVC count <120/h on Holter (area under the curve 0.80, sensitivity 83.9%, specificity 74.3%, for ≥2 h). Only F-HR-PVC patients responded to isoproterenol. Isoproterenol washout or phenylephrine infusion was successful for the 3 S-HR-PVC patients, and no drug could increase PVC frequency in the 12 I-HR-PVC patients. Long-term RFA success rate in patients with frequent PVCs at baseline (82.9%) was similar to those with infrequent PVC who responded to a drug (77.8%; P = .732) but significantly higher than for those who did not respond to any drug (15.4%; P <.0001). Conclusion A simple analysis of Holter PVC circadian variability provides incremental value to guide pharmacologic induction of PVCs during RFA and predict outcome. Patients with infrequent I-HR-PVC had the least successful outcomes from RF ablation

Programmed death ligand-1 expression on donor T cells drives graft-versus-host disease lethality

Programmed death ligand-1 (PD-L1) interaction with PD-1 induces T cell exhaustion and is a therapeutic target to enhance immune responses against cancer and chronic infections. In murine bone marrow transplant models, PD-L1 expression on host target tissues reduces the incidence of graft-versus-host disease (GVHD). PD-L1 is also expressed on T cells; however, it is unclear whether PD-L1 on this population influences immune function. Here, we examined the effects of PD-L1 modulation of T cell function in GVHD. In patients with severe GVHD, PD-L1 expression was increased on donor T cells. Compared with mice that received WT T cells, GVHD was reduced in animals that received T cells from Pdl1–/– donors. PD-L1–deficient T cells had reduced expression of gut homing receptors, diminished production of inflammatory cytokines, and enhanced rates of apoptosis. Moreover, multiple bioenergetic pathways, including aerobic glycolysis, oxidative phosphorylation, and fatty acid metabolism, were also reduced in T cells lacking PD-L1. Finally, the reduction of acute GVHD lethality in mice that received Pdl1–/– donor cells did not affect graft-versus-leukemia responses. These data demonstrate that PD-L1 selectively enhances T cell–mediated immune responses, suggesting a context-dependent function of the PD-1/PD-L1 axis, and suggest selective inhibition of PD-L1 on donor T cells as a potential strategy to prevent or ameliorate GVHD

pH dependence of a 3<SUB>10</SUB>-helix versus a turn in the M-loop region of PDE4: observations on PDB entries and an electronic structure study

Available X-ray crystal structures of phosphodiesterase 4 (PDE 4) are classified into two groups based on a secondary structure difference of a 310-helix versus a turn in the M-loop region. The only variable that was discernible between these two sets is the pH at the crystallization conditions. Assuming that at lower pH there is a possibility of protonation, thermodynamics of protonation and deprotonation of the aspartic acid, cysteine side chains, and amide bonds are calculated. The models in the gas phase and in the explicit solvent using the ONIOM method are calculated at the B3LYP/6-31+G&#8727; and B3LYP/6-31+G&#8727;:UFF levels of theory, respectively. The molecular dynamics (MD) simulations are also performed on the M-loop region of a 310-helix and a turn with explicit water for 10 ns under NPT conditions. The isodesmic equations of the various protonation states show that the turn containing structure is thermodynamically more stable when proline or cysteine is protonated. The preference for the turn structure on protonation (pH = 6.5-7.5) is due to an increase in the number of the hydrogen bonding and electrostatic interactions gained by the surrounding environment such as adjacent residues and solvent molecules

pH Dependence of a 3103_{10}-Helix versus a Turn in the M-Loop Region of PDE4: Observations on PDB Entries and an Electronic Structure Study

Available X-ray crystal structures of phosphodiesterase 4 (PDE 4) are classified into two groups based on a secondary structure difference of a $3_{10}$-helix versus a turn in the M-loop region. The only variable that was discernible between these two sets is the pH at the crystallization conditions. Assuming that at lower pH there is a possibility of protonation, thermodynamics of protonation and deprotonation of the aspartic acid, cysteine side chains,and amide bonds are calculated. The models in the gas phase and in the explicit solvent using the ONIOM method are calculated at the B3LYP/6-31+G* and B3LYP/6-31+G*:UFF levels of theory, respectively. The molecular dynamics (MD) simulations are also performed on the M-loop region of a $3_{10}$-helix and a turn with explicit water for 10 ns under NPT conditions. The isodesmic equations of the various protonation states show that the turn containing structure is thermodynamically more stable when proline or cysteine is protonated. The preference for the turn structure on protonation (pH = 6.5-7.5) is due to an increase in the number of the hydrogen bonding and electrostatic interactions gained by the surrounding environment such as adjacent residues and solvent molecules

Subtype Selectivity in Phosphodiesterase 4 (PDE4): A Bottleneck in Rational Drug Design

Subtype selectivity of phosphodiesterase 4 (PDE4) has been proposed to be the most salient feature for the development of drugs for asthma and inflammation. The present review provides an account of various strategies to overcome the side effects of the PDE4 inhibitors. Subtype selectivity and recent developments of molecular modeling approaches towards PDE4 were addressed using QSAR and docking, followed by a detailed structural analysis of more than three dozen available X-ray structures of PDE4B and PDE4D. Usually, the lack of a 3-dimensional structure of a target protein is a bottleneck for rational drug design approaches. However, in this case the availability of 39 X-ray structures along with co-crystals has not improved the therapeutic ratio of drugs through rational drug design approaches. The investigation of structures led to find significant variations in the M-loop region, which is the integral part of the active site of PDE4B and PDE4D. These differences can be accounted for by varying conformation of the Pro(430) residue and a Thr(436)/Asn(362) mutation in the M-loop that causes variations in adjacent residue properties and also the pattern of hydrogen-bonding interactions. The impact of the M-loop region on inhibitor binding has been further scrutinized by MOLCAD surfaces and hydrophobicity. These have shown that PDE4B is more hydrophobic in nature than PDE4D in the M-loop region. A review of the above aspects given the emphasis on a new PDE4 inhibitor which can access both metal and solvent pockets may possibly lead to ligands with enhanced potency. The lining of the Q2 pocket that involves the M-loop region may be considered for the design of potent subtype-selective inhibitors